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Background: Little is known about rates of COVID-19 vaccine uptake among youth with bipolar spectrum disorders (BSD). As such, the aim of this study is to assess rates and predictors of COVID-19 vaccine uptake among youth with BSD and their caregivers in the United States., Methods: Youth and their main caregiver were recruited from a large pragmatic study cohort. Youth who were aged 8-22 at the time of this data collection, had a bipolar-spectrum disorder diagnosis, had overweight or obesity, and were treated with a second-generation antipsychotic were invited to participate in an online survey and interview assessing the impact of the COVID-19 pandemic., Results: A total of 453 surveys and 341 interviews were completed 07/2021-05/2022 by youth and their caregivers. Sixty-seven percent of caregivers and 63 % of youth reported receiving the COVID-19 vaccine. Vaccine uptake rates among youth and caregivers were highly correlated. Predictors of vaccine uptake among youth were older age and living in the Northeast Region of the United States. Predictors of caregiver vaccine uptake were male sex, higher annual household income and not having to quarantine due to COVID-19., Limitations: The sample was small and not a full representation of a population with bipolar-spectrum disorders therefore, the results may not be generalizable. The study design and statistical method do not allow for causal inferences to be made., Conclusions: These findings may aid in targeting interventions to maximize COVID-19 and other vaccine uptake in youth with bipolar disorders and their families., Competing Interests: Declaration of competing interest Author Disclosures: Dr. DelBello has received research support from Allergan, Alkermes, Janssen, Johnson and Johnson, Lundbeck, Myriad, NIMH, Otsuka, PCORI, Pfizer, Shire, and Sunovion. She has received consulting/advisory/board/honoraria support from Alkermes, CMEology, Johnson and Johnson, Medscape, Myriad, and Sage. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen,Takeda and PCORI. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. Dr. Patino has received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion, and Shire. Drs. Klein, Welge, Fornari, and Higdon and Mr. Blom received salary support from PCORI. Ms. Keller and Ms. Wingler declare they have no financial interests. This study was funded by: PCORI Award Number: PCS-1406-19276., (Published by Elsevier B.V.)

Objective: Youth with bipolar spectrum disorders (BSD) are frequently prescribed second-generation antipsychotics (SGAs). Nonadherence to treatment often results in increased mood symptoms and diminished quality of life. We examined SGA adherence rates and adherence barriers among youth who have overweight/obesity and are diagnosed with BSD enrolled in a multisite pragmatic clinical trial. Methods: SGA adherence and adherence barriers at baseline via patient- and caregiver report was assessed. Adherence was defined as taking ≥70% of prescribed SGA doses in the past week. The weighted Kappa statistic was used to measure child-caregiver agreement about adherence rates, barriers, and caregiver assistance. Regression analyses were used to examine associations of caregiver assistance, age, sex, race, insurance status, dosing frequency, and number of concomitant medications with adherence. Barriers to adherence were analyzed separately for youth and their caregivers, using logistic regression to assess associations between informant-reported barriers and informant-reported adherence. Results: Participants included 1485 patients and/or caregivers. At baseline, 88.6% of patients self-reported as adherent; 92.0% of caregivers reported their child was adherent. Concordance between patients and caregivers was moderate ( k = 0.42). Approximately, 50% of the sample reported no adherence barriers. Frequently endorsed barriers included forgetting, side effects, being embarrassed to take medications, and preferring to do something else. Concordance between informants regarding adherence barriers was weak ( k = 0.05-0.36). Patients and caregivers who did not endorse adherence barriers reported higher adherence than those who endorsed barriers. Male sex and having once daily dosing of medications were associated with lower adherence. Discussion: One-week patient- and caregiver-reported adherence was high in this sample. Half of the sample reported adherence barriers. Most commonly endorsed barriers were forgetting, side effects, being embarrassed, and preferring to do something else. Caregivers and patients have unique perspectives regarding adherence barriers. Understanding and addressing treatment barriers in clinical practice may facilitate adherence.

P38 mitogen-activated protein kinases are key in the regulation of the cellular response to stressors. P38 is known to regulate transcription, mRNA processing, stability, and translation. The transcriptional changes mediated by phosphorylated p38 (P-p38) in response to extracellular stimuli have been thoroughly analyzed in many tissues and organisms. However, the genomic localization of chromatin-associated P-p38 remains poorly understood. Here, we analyze the chromatin binding of activated P-p38 and its role in the response to reactive oxygen species (ROS) in Drosophila S2 cells. We found that P-p38 is already bound to chromatin in basal conditions. After ROS exposure, chromatin-associated P-p38 relocates towards genes involved in the recovery process. Our findings highlight the role of P-p38 dynamic chromatin binding in orchestrating gene expression responses to oxidative stress., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A neonatal intensive care unit (NICU) hospitalization can add significant stress to the postpartum period. Parents experience isolation and uncertainty, which can affect their capacity to bond with their new baby. Understanding how stress is shaped by and changes following a NICU experience will help in developing supports for these families. We examined patterns of parenting stress over the first year of life following a NICU stay to better understand changes in stress, differences in maternal and paternal stress, and how medical and developmental variables impact parent stress. Parents of infants ( n = 51) who had experienced a NICU hospitalization and met criteria for California's High-Risk Infant Follow-Up program completed assessments at 6, 9, and 12 months. A comparison group ( n = 38) from a historic dataset included parents of infants born full term without medical complications. NICU parents reported higher levels of parenting stress at 6 months, but not 12 months, with mothers and fathers reporting similar stress levels. Parenting-related stress was found to be relatively stable and consistent over this period. Among NICU parents, lower developmental level at 12 months was associated with more distress in interacting with their child. These findings highlight the importance of monitoring parenting stress following discharge from the NICU and developing interventions for supporting parents of NICU graduates showing developmental delays.

Therapist anxious distress when delivering child mental health treatment has been understudied as a factor that contributes to the underuse of some evidence-based interventions (EBIs), such as time-out for children with disruptive behaviors. This study investigated therapist anxious avoidance of time-out using a three-part, vignette-based survey design. Therapists (n = 198) read a vignette of an in-session time-out and reported on their personal anxious distress and likelihood of discontinuing the implementation of time-out. Therapists also provided open-ended descriptions of challenges to delivering time-out. Therapists reported moderate anxious distress at time points 1 and 2 and lower anxious distress at time 3 when the time-out had resolved. Most therapists endorsed some avoidance of time-out. Binomial logistic regression analyses indicated that increased anxious distress corresponded with an increased probability of avoiding time-out delivery in the future. Qualitative reports expanded on challenges to implementing time-out. Findings suggest the importance of addressing therapist anxious distress when implementing children's mental health treatments., (© 2024. The Author(s).)

Language is bounded to the left hemisphere in the adult brain and the functional lateralization can already be observed early during development. Here we investigate whether this is paralleled by a lateralization of the white matter structural language network. We analyze the strength and microstructural properties of language-related fiber tracts connecting temporal and frontal cortices with a separation of two dorsal tracts, one targeting the posterior Broca's area (BA44) and one targeting the precentral gyrus (BA6). In a large sample of young children (3-6 years), we demonstrate that, in contrast to the BA6-targeting tract, the microstructural asymmetry of the BA44-targeting fiber tract significantly correlates locally with different aspects of development. While the asymmetry in its anterior segment reflects age, the asymmetry in its posterior segment is associated with the children's language skills. These findings demonstrate a fine-grained structure-to-function mapping in the lateralized network and go beyond our current view of language-related human brain maturation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To characterize the neuroanatomy of BD in youth and its correlation to clinical characteristics., Methods: The current study includes a sample of 105 unmedicated youth with first-episode BD, aged between 10.1 and 17.9 years, and 61 healthy comparison adolescents, aged between 10.1 and 17.7 years, who were matched for age, race, sex, socioeconomic status, intelligence quotient (IQ), and education level. T1-weighted magnetic resonance imaging (MRI) images were obtained using a 4 T MRI scanner. Freesurfer (V6.0) was used to preprocess and parcellate the structural data, and 68 cortical and 12 subcortical regions were considered for statistical comparisons. The relationship between morphological deficits and clinical and demographic characteristics were evaluated using linear models., Results: Compared with healthy youth, youth with BD had decreased cortical thickness in frontal, parietal, and anterior cingulate regions. These youth also showed decreased gray matter volumes in 6 of the 12 subcortical regions examined including thalamus, putamen, amygdala and caudate. In further subgroup analyses, we found that youth with BD with comorbid attention-deficit hyperactivity disorder (ADHD) or with psychotic symptoms had more significant deficits in subcortical gray matter volume., Limitations: We cannot provide information about the course of structural changes and impact of treatment and illness progression., Conclusions: Our findings indicate that youth with BD have significant neurostructural deficits in both cortical and subcortical regions mainly located in the regions related to emotion processing and regulation. Variability in clinical characteristics and comorbidities may contribute to the severity of anatomic alterations in this disorder., Competing Interests: Declaration of competing interest Dr. Strawn has received research support from the National Institutes of Health (NIMH/NIEHS/NICHD) as well as Allergan, Neuronetics and Otsuka. He has received material support from and provided consultation to Myriad Genetics and receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. He has spoken in CME presentations for Neuroscience Education Institute and CMEology. Dr. Strawn also has provided consultation to the FDA and Intracellular Therapeutics. Dr. Sweeney consults to VeriSci. Dr. Patino and Dr. DelBello have received research support from NIMH, PCORI, Acadia, Alkermes, Allergan, Janssen, Johnson and Johnson, Lundbeck, Myriad, Otsuka, Pfizer, Sunovion and Shire. Dr. DelBello has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson and Johnson, Lundbeck, Medscape, Myriad, Pfizer, Sage, and Sunovion. All other authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The purpose is to compare youth- and caregiver-reported characteristics of family environment, within and between families with a child experiencing a first manic episode of bipolar disorder (BPD), and families without a child with BPD or familial history of psychiatric disorders (HF)., Methods: Family environment of 61 families with a child with BPD and 44 HF were assessed with Family Environment Scale (FES). We compared FES subscale scores between families with BPD and HF, and caregiver- and youth-rated scores., Results: Families with BPD differed significantly from HF on 8/10 FES subscales scores. Youth differed significantly from their caregivers on 7/10 subscales. An interaction effect was observed such that youth with BPD reported lower cohesion and organization, and higher conflict than their caregivers; however, HF did not differ significantly on these domains., Conclusions: Our results suggest that families with BPD have higher conflict and lower cohesion and organization compared to HF. Results also indicate differences between youth and caregiver perspectives in both groups, which may contribute to family discord. Interventions targeting areas of cohesion, organization, and conflict may be beneficial for youth with BPD and their families, specifically those that identify and bridge perceptual divides.

Background: Identification of treatment-specific predictors of drug therapies for bipolar disorder (BD) is important because only about half of individuals respond to any specific medication. However, medication response in pediatric BD is variable and not well predicted by clinical characteristics., Methods: A total of 121 youth with early course BD (acute manic/mixed episode) were prospectively recruited and randomized to 6 weeks of double-blind treatment with quetiapine ( n = 71) or lithium ( n = 50). Participants completed structural magnetic resonance imaging (MRI) at baseline before treatment and 1 week after treatment initiation, and brain morphometric features were extracted for each individual based on MRI scans. Positive antimanic treatment response at week 6 was defined as an over 50% reduction of Young Mania Rating Scale scores from baseline. Two-stage deep learning prediction model was established to distinguish responders and non-responders based on different feature sets., Results: Pre-treatment morphometry and morphometric changes occurring during the first week can both independently predict treatment outcome of quetiapine and lithium with balanced accuracy over 75% (all p < 0.05). Combining brain morphometry at baseline and week 1 allows prediction with the highest balanced accuracy (quetiapine: 83.2% and lithium: 83.5%). Predictions in the quetiapine and lithium group were found to be driven by different morphometric patterns., Conclusions: These findings demonstrate that pre-treatment morphometric measures and acute brain morphometric changes can serve as medication response predictors in pediatric BD. Brain morphometric features may provide promising biomarkers for developing biologically-informed treatment outcome prediction and patient stratification tools for BD treatment development.

In recent years, the prevalence rates of children's mental health disorders have increased with current estimates identifying that as many as 15-20% of children meet criteria for a mental health disorder. Unfortunately, the same robust parenting interventions which have long targeted some of the most common and the most treatable child concerns (e.g., externalizing, disruptive behavior, and aggression) have also shown consistently low rates of father engagement. This persistent issue of engagement comes in the wake of an increasingly large body of literature which highlights the unique positive contributions fathers make to children and families when they are engaged in parenting interventions. As the role fathers play in families shifts to become more inclusive of childcare responsibilities and less narrowly defined by financial contributions, it becomes increasingly important to understand how best to engage fathers in interventions that aim to enhance parenting efficacy and family outcomes such as coparenting. The current review examined intervention (e.g., format and setting) and implementation characteristics (e.g., training and agency-level changes) associated with father engagement. Particular attention is paid to studies which described father-specific engagement strategies (e.g., inviting fathers directly, father-only groups, and adapting intervention to incorporate father preferences). A total of 26 articles met inclusion criteria after screening and full-text review. Results indicate that father engagement (i.e., initiating treatment) remains low with 58% of studies either not reporting father engagement or having engagement rates below 50%. More than two-thirds of studies did not include specific father engagement strategies. Those that did focused on changes to treatment format (e.g., including recreational activities), physical treatment setting (e.g., in-home and school), and reducing the number of sessions required for father participation as the most common father-specific engagement strategies. Some studies reported efforts to target racially and ethnically diverse fathers, but review results indicated most participants identified as Non-Hispanic White. Interventions were largely standard behavioral parent training programs (e.g., PCIT and PMT) with few exceptions (e.g., COACHES and cultural adaptations), and very few agencies or programs are systematically making adjustments (e.g., extended clinic hours and changes to treatment format) to engage fathers. Recommendations for future directions of research are discussed including the impact of differential motivation on initial father engagement in treatment, the importance of continuing to support diverse groups of fathers, and the potential for telehealth to address barriers to father engagement., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Within the first years of life, children learn major aspects of their native language. However, the ability to process complex sentence structures, a core faculty in human language called syntax, emerges only slowly. A milestone in syntax acquisition is reached around the age of 4 years, when children learn a variety of syntactic concepts. Here, we ask which maturational changes in the child's brain underlie the emergence of syntactically complex sentence processing around this critical age. We relate markers of cortical brain maturation to 3- and 4-year-olds' sentence processing in contrast to other language abilities. Our results show that distinct cortical brain areas support sentence processing in the two age groups. Sentence production abilities at 3 years were associated with increased surface area in the most posterior part of the left superior temporal sulcus, whereas 4-year-olds showed an association with cortical thickness in the left posterior part of Broca's area, i.e. BA44. The present findings suggest that sentence processing abilities rely on the maturation of distinct cortical regions in 3- compared to 4-year-olds. The observed shift to more mature regions involved in processing syntactically complex sentences may underlie behavioral milestones in syntax acquisition at around 4 years., (© The Author(s) 2022. Published by Oxford University Press.)

Disruptions in the limbic system, and in emotion regulation circuitry that supports affect modulation, have been reported during acute manic episodes of bipolar disorder (BD). The impact of pharmacological treatment on these deficits, especially in youth, remains poorly characterized. 107 youths with acute manic or mixed episodes of bipolar I disorder and 60 group-matched healthy controls were recruited. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. Task-based fMRI studies were performed using an identical pairs continuous performance task (CPT-IP) at pre-treatment baseline and post-treatment weeks one and six. Region of interest analyses focused on the limbic system and ventral PFC - basal ganglia - thalamocortical loop structures known to be involved in emotion regulation. Changes in regional activation were compared between the two treatment groups, and pretreatment regional activation was used to predict treatment outcome. Mania treatment scores improved more rapidly in the quetiapine than lithium treated group, as did significant normalization of neural activation toward that of healthy individuals in left amygdala (p = 0.007), right putamen (p < 0.001), and right globus pallidus (p = 0.003). Activation changes in the right putamen were correlated with reduction of mania symptoms. The limbic and emotion regulation system activation at baseline and week one predicted treatment outcome in youth with bipolar disorder with significant accuracy (up to 87.5%). Our findings document more rapid functional brain changes associated with quetiapine than lithium treatment in youth with bipolar disorder, with most notable changes in the limbic system and emotion regulation circuitry. Pretreatment alterations in these regions predicted treatment response. These findings advance understanding of regional brain alterations in youth with bipolar disorder, and show that fMRI data can predict treatment outcome before it can be determined clinically, highlighting the potential utility of fMRI biomarkers for early prediction of treatment outcomes in bipolar disorder.Clinical Trials Registration: Name: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania. URL: https://clinicaltrials.gov/ . Registration number: NCT00893581., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Parent-Child Interaction Therapy (PCIT) is an evidence-based practice that effectively prevents and treats child disruptive behaviors and child physical maltreatment and reduces parenting stress. PCIT was adapted for telehealth delivery, internet-delivered PCIT (iPCIT), before the COVID-19 pandemic but was not widely implemented until the rapid transition to telehealth during stay-at-home orders. To understand how clinicians adapted PCIT during COVID-19, we followed up on a previous study investigating community clinician adaptations of PCIT pre-COVID-19 using the Lau et al. (2017) Augmenting and Reducing Framework. Clinicians ( N = 179) who responded to the follow-up survey and reported delivering PCIT remotely completed a quantitative measure of adaptations at both time points (Fall 2019; Summer 2020) to assess how adaptations to PCIT changed following lockdown measures. Clinicians ( n = 135) also provided qualitative descriptions of adaptations made early in the COVID-19 pandemic. Clinicians in the full sample were 74.3% Non-Hispanic White and 14% Latinx. Most clinicians had a master's degree (66.5%), were licensed (80.4%), and were PCIT-certified (70.4%). Paired samples t-tests showed that clinicians reported similar levels of augmenting t (179) = -0.09, p=.926) and reducing adaptations t (179) = -0.77, p =.442) at both time points. Unlike quantitative findings, qualitative findings indicated that clinicians described engaging in many types of adaptations in response to the pandemic. Clinicians discussed engaging in augmenting adaptations by extending treatment length and integrating other practices into treatment. Clinicians also discussed engaging in reducing adaptations. Implications and future directions will be discussed.

Parent-Child Interaction Therapy (PCIT) is an evidence-based practice (EBP) for young children with challenging behaviors. PCIT has been adapted to treat varying presentations and culturally diverse families. Although efforts have been made to disseminate PCIT into community settings, which often serve clinically complex, socio-culturally diverse, and marginalized communities, barriers to disseminating adapted models remain. An alternative strategy to understanding how to increase access to appropriately adapted PCIT is to learn from community clinicians' practice-based adaptations to meet their clients' diverse needs related to clinical presentation, culture, and language. This mixed-method study investigated community clinician adaptations of PCIT. Clinicians ( N = 314) were recruited via PCIT listservs to complete a survey collecting background information, and adaptations to PCIT. Most clinicians had a master's degree (72.1%), were licensed (74.2%), and were PCIT-certified (70.7%). Qualitative interviews were conducted with a purposeful sample of 23 community clinicians, who were 39% Spanish-speaking, were 30% Latinx, and 30% reported serving a ≥50% Latinx clientele. Clinicians reported engaging in adaptations aimed at augmenting PCIT more extensively than adaptations involving removing core components. Themes from qualitative interviews converged with quantitative findings, with clinicians most frequently describing augmenting adaptations, and highlighted reasons for adapting PCIT. Clinicians primarily augmented treatment to address clients' clinical presentations. Clinicians rarely adapted treatment specifically for culture, but when mentioned, clinicians discussed tailoring idioms and phrases to match clients' culture for Spanish-speaking clients. Implications for training PCIT clinicians in intervention adaptations will be discussed.

Engaging caregivers in their children's mental health treatment is critical for delivering high quality, evidence-based care, particularly for young children with externalizing behaviors. Lay health workers (LHWs), including peer providers and promotoras de salud , have been identified as important workforces in addressing structural and stigma-related barriers to engagement in mental health services. Importantly, research has suggested that LHWs may be integral in efforts to address engagement disparities in evidence-based behavioral parent training programs (BPTs) for Latinx caregivers. The purpose of the study was to understand how different LHW workforces engage caregivers within their usual services, in order to inform strategies that improve access to and engagement in BPTs. Qualitative interviews were conducted with two different LHW workforces: volunteer LHWs (i.e., promotoras de salud ) ( n = 14), who were part of a community-embedded network, and paid LHWs (i.e., parent support partners, home visitors) ( n = 9) embedded within children's mental health agencies. Participants were predominately Latinx (79%) and female (96%). Qualitative analyses revealed three primary themes related to engagement strategies used by LHWs to address barriers to care: 1.) Building Trust, 2.) Empowerment, 3.) Increasing Access. Although the majority of themes and sub-themes were consistent across the two LHW workforces, agency-embedded LHWs often discussed having the means to provide resources through their organizations, whereas community-embedded LHWs discussed acting as a bridge to services by providing information and conducting outreach. Findings have implications for partnering with different workforces of LHWs to increase equity in access to BPTs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to disclose.

Objective: Disruptions in cognition are a clinically significant feature of bipolar disorder (BD). The effects of different treatments on these deficits and the brain systems that support them remain to be established., Method: A continuous performance test was administered to 55 healthy controls and 71 acutely ill youths with mixed/manic BD to assess vigilance and working memory during task-based functional magnetic resonance imaging studies. Patients, who were untreated for at least 7 days at baseline, and controls were scanned at pretreatment baseline and at weeks 1 and 6. After baseline testing, patients (n = 71) were randomly assigned to 6-week double-blind treatment with lithium (n = 26; 1.0-1.2 mEq/L) or quetiapine (n = 45; 400-600 mg). Weighted seed-based connectivity (wSBC) was used to assess regional brain interactions during the attention task compared with the control condition., Results: At baseline, youths with BD showed reduced connectivity between bilateral anterior cingulate cortex and both left ventral lateral prefrontal cortex and left insula and increased connectivity between left ventral lateral prefrontal cortex and left temporal pole, left orbital frontal cortex and right postcentral gyrus, and right amygdala and right occipital pole compared with controls. At 1-week follow-up, quetiapine, but not lithium, treatment led to a significant shift of connectivity patterns toward those of the controls. At week 6, compared with baseline, there was no difference between treatment conditions, at which time both patient groups showed significant normalization of brain connectivity toward that of controls., Conclusion: Functional alterations in several brain regions associated with cognitive processing and the integration of cognitive and affective processing were demonstrated in untreated youths with BD before treatment. Treatment reduced several of these alterations, with significant effects at week 1 only in the quetiapine treatment group. Normalization of functional connectivity might represent a promising biomarker for early target engagement in youth with BD., Clinical Trial Registration Information: Multimodal Neuroimaging of Treatment Effects in Adolescent Mania; https://clinicaltrials.gov/; NCT00893581., (Published by Elsevier Inc.)

Over the last decade, the increasing interest in long non-coding RNAs (lncRNAs) has led to the discovery of these transcripts in multiple organisms. LncRNAs tend to be specifically, and often lowly, expressed in certain tissues, cell types and biological contexts. Although lncRNAs participate in the regulation of a wide variety of biological processes, including development and disease, most of their functions and mechanisms of action remain unknown. Poor conservation of the DNA sequences encoding for these transcripts makes the identification of lncRNAs orthologues among different species very challenging, especially between evolutionarily distant species such as flies and humans or mice. However, the functions of lncRNAs are unexpectedly preserved among different species supporting the idea that conservation occurs beyond DNA sequences and reinforcing the potential of characterising lncRNAs in animal models. In this review, we describe the features and roles of lncRNAs in the fruit fly Drosophila melanogaster, focusing on genomic and functional comparisons with human and mouse lncRNAs. We also discuss the current state of advances and limitations in the study of lncRNA conservation and future perspectives., (© 2021. The Author(s).)

This paper posits that a clinician's own anxious reaction to delivering specific evidence-based interventions (EBIs) should be better accounted for within implementation science frameworks. A key next step for implementation science is to delineate the causal processes most likely to influence successful implementation of evidence-based interventions (EBIs). This is critical for being able to develop tailored implementation strategies that specifically target mechanisms by which implementation succeeds or fails. First, we review the literature on specific EBIs that may act as negatively valenced stimuli for clinicians, leading to a process of clinician maladaptive anxious avoidance that can negatively impact EBI delivery. In the following sections, we argue that there are certain EBIs that can cause emotional distress or discomfort in a clinician, related to either: (1) a clinicians' fear of the real or predicted short-term distress the EBI can cause patients, or (2) fears that the clinician will inadvertently cause the patient harm and/or face liability. This distress experienced by the clinician can perpetuate a cycle of maladaptive anxious avoidance by the clinician, contributing to lack of or suboptimal EBI implementation. We illustrate how this cycle of maladaptive anxious avoidance can influence implementation by providing several examples from leading EBIs in the psychosocial literature. To conclude, we discuss how leveraging decades of treatment literature aimed at mitigating maladaptive anxious avoidance can inform the design of more tailored and effective implementation strategies for EBIs that are negatively valenced., Competing Interests: Conflicts of Interest. Dr. Oquendo and Dr. Brown receive royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. Dr. Oquendo serves as an advisor to Alkermes, Otsuka, ATAI, St. George’s University and Fundacion Jimenez Diaz; her family owns stock in Bristol Myers Squibb. All other authors have no conflict of interest to disclose. Dr. Brown serves as an advisor for Oui Therapeutics, LLC and Psych Hub, LLC. All other authors declare that there is no conflict of interest.

Progress measures are an evidence-based technique for improving the quality of mental health care, however, clinicians rarely incorporate them into treatment. Research into how measure type impacts clinician preference has been recommended to help improve measure implementation. Parent-Child Interaction Therapy (PCIT) is an assessment-driven treatment that serves as an ideal intervention through which to investigate measure preferences given its routine use of two types of assessments, a behavioral observation (the Dyadic Parent-Child Interaction Coding System) and a parent-report measure (the Eyberg Child Behavior Inventory). This study investigated PCIT therapist attitudes towards progress measures used within PCIT and children's mental health treatment generally. A mixed-method (QUAN + QUAL) study design examined PCIT therapist attitudes towards two types of progress measures and measures used in two contexts (PCIT and general practice). Multi-level modeling of a survey distributed to 324 PCIT therapists identified predictors of therapist attitudes towards measures, while qualitative interviews with 23 therapists expanded and clarified the rationale for differing perceptions. PCIT therapists reported more positive attitudes towards a behavioral observation measure, the DPICS, than a parent-report measure, the ECBI, and towards measures used in PCIT than in general practice. Clinician race/ethnicity was significantly related to measure-specific attitudes. Qualitative interviews highlighted how perceptions of measure reliability, type of data offered, ease of use, utility in guiding sessions and motivating clients, and embeddedness in treatment protocol impact therapist preferences. Efforts to implement progress monitoring should consider preferences for particular types of measures, as well as how therapists are trained to embed measures in treatment., (© 2021. The Author(s).)

Objective: To compare the efficacy and tolerability of lithium versus quetiapine for the treatment of manic or mixed episodes in youths with early course bipolar I disorder. Methods: Six-week, randomized, double-blind clinical trial of lithium versus quetiapine for the treatment of adolescents with acute manic/mixed episode. Target dose of quetiapine dose was adjusted to a target dose of 400-600 mg and target serum level for lithium was 1.0-1.2 mEq/L. Primary outcome measure was baseline-to-endpoint change in the Young Mania Rating Scale (YMRS). Secondary outcomes were treatment response (50% or more decrease from baseline in YMRS score) and remission (YMRS score ≤12, Children's Depression Rating Scale-Revised [CDRS-R] total score ≤28 and Clinical Global Impression Bipolar Severity Scale [CGI-BP-S] overall score of ≤3, respectively). Results: A total of 109 patients were randomized (quetiapine = 58 and lithium = 51). Participants in the quetiapine treatment group showed a significantly greater reduction in YMRS score than those in the lithium group (-11.0 vs. -13.2; p  < 0.001; effect size 0.39). Response rate was 72% in the quetiapine group and 49% in the lithium group ( p  = 0.012); no differences in remission rates between groups were observed. Most frequent side effects for lithium were headaches (60.8%), nausea (39.2%), somnolence (27.5%), and tremor (27.5%); for quetiapine somnolence (63.8%), headaches (55.2%), tremor (36.2%), and dizziness (36.2%) were evidenced. Participants receiving quetiapine experienced more somnolence ( p  < 0.001), dizziness ( p  < 0.05), and weight gain ( p  < 0.05). Conclusions: Treatment with both lithium and quetiapine led to clinical improvement. Most study participants in this study experienced a clinical response; however, less than half of the participants in this study achieved symptomatic remission. The head-to-head comparison of both treatment groups showed quetiapine was associated with a statistically significant greater rate of response and overall symptom reduction compared with lithium. Trial registration: clinicaltrials.gov NCT00893581.

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (C p ) (p = 0.009) and characteristic path length (L p ) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. C p , L p , and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

Natural Antisense Transcripts (NATs) are long non-coding RNAs (lncRNAs) that overlap coding genes in the opposite strand. NATs roles have been related to gene regulation through different mechanisms, including post-transcriptional RNA processing. With the aim to identify NATs with potential regulatory function during fly development, we generated RNA-Seq data in Drosophila developing tissues and found bsAS, one of the most highly expressed lncRNAs in the fly wing. bsAS is antisense to bs/DSRF, a gene involved in wing development and neural processes. bsAS plays a crucial role in the tissue specific regulation of the expression of the bs/DSRF isoforms. This regulation is essential for the correct determination of cell fate during Drosophila development, as bsAS knockouts show highly aberrant phenotypes. Regulation of bs isoform usage by bsAS is mediated by specific physical interactions between the promoters of these two genes, which suggests a regulatory mechanism involving the collision of RNA polymerases transcribing in opposite directions. Evolutionary analysis suggests that bsAS NAT emerged simultaneously to the long-short isoform structure of bs, preceding the emergence of wings in insects., Competing Interests: The authors have declared that no competing interests exist.

The molecular complexity of human breast cancer (BC) renders the clinical management of the disease challenging. Long non-coding RNAs (lncRNAs) are promising biomarkers for BC patient stratification, early detection, and disease monitoring. Here, we identified the involvement of the long intergenic non-coding RNA 01087 (LINC01087) in breast oncogenesis. LINC01087 appeared significantly downregulated in triple-negative BCs (TNBCs) and upregulated in the luminal BC subtypes in comparison to mammary samples from cancer-free women and matched normal cancer pairs. Interestingly, deregulation of LINC01087 allowed to accurately distinguish between luminal and TNBC specimens, independently of the clinicopathological parameters, and of the histological and TP53 or BRCA1/2 mutational status. Moreover, increased expression of LINC01087 predicted a better prognosis in luminal BCs, while TNBC tumors that harbored lower levels of LINC01087 were associated with reduced relapse-free survival. Furthermore, bioinformatics analyses were performed on TNBC and luminal BC samples and suggested that the putative tumor suppressor activity of LINC01087 may rely on interferences with pathways involved in cell survival, proliferation, adhesion, invasion, inflammation and drug sensitivity. Altogether, these data suggest that the assessment of LINC01087 deregulation could represent a novel, specific and promising biomarker not only for the diagnosis and prognosis of luminal BC subtypes and TNBCs, but also as a predictive biomarker of pharmacological interventions., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The objective of this research was to understand physician, patient, and parent perspectives on barriers to second-generation antipsychotic (SGA) medication adherence in youth with bipolar spectrum disorders, and attitudes toward treatment of SGA-related weight gain. Methods: Patients diagnosed with bipolar disorder before age 18, parents of children diagnosed before 18, and clinicians with experience prescribing SGAs for these patients completed surveys regarding SGA-related side effects, adherence barriers, and acceptability of weight management strategies. Results: Patients ( n  = 225), parents ( n  = 128), and clinicians ( n  = 54) reported weight gain as the most concerning SGA-related side effect (45.6%, 38.9%, and 70.4%, respectively). Weight gain was also the top adherence barrier for patients (35.9%), but was ranked fourth (41.8%) by parents. Patients (61.5%) were more likely "definitely" willing to co-initiate another medication to manage weight gain upon SGA initiation than parents (20.1%) or clinicians (1.9%). Conversely, parents (54.9%) and clinicians (84.9%) were "definitely" willing to accept/prescribe a second medication aiming to reverse weight gain of ≥10 lbs., and patients (61.1%) were willing to add another medication to reverse any weight gain. Conclusion: SGA-related weight gain impairs medication adherence in young patients with bipolar disorder. Many young patients would start pharmacologic treatment to mitigate SGA-related weight gain at treatment initiation, parents and clinicians are more hesitant. This research informs patient-centered perspectives on SGA adherence barriers and strategies to minimize potential side effects, which may improve adherence in this vulnerable patient population.

Objectives: To examine metabolic monitoring rates in commercially insured children and adolescents treated with a second-generation antipsychotic (SGA) during calendar years (CYs) 2016 and 2017. Methods: In this retrospective study, data were collected from a large national commercial health plan for the period covering January 1, 2016 to December 31, 2017. Commercially insured children and adolescents, aged 8-19 years with ≥2 SGA prescription claims during the CY, were identified for the CY2016 and CY2017 cohorts. The primary outcome of interest was the percentage of subjects with any glucose or lipid metabolism parameter monitoring. Other calculated metabolic testing rates included glucose, hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), other cholesterol (including triglycerides), and combined glucose and lipid metabolism testing (≥1 test for blood glucose or HbA1c and ≥1 test for LDL-C or other cholesterol). Results: In CY2016 and CY2017, 1502 and 1239 subjects, respectively, were identified for this study. The most common psychiatric diagnoses in CY2016 and CY2017 were major depressive disorder (57.1%, 56.5%, respectively), anxiety disorders (42.9%, 47.5%), attention-deficit/hyperactivity disorder (41.6%, 45.8%), and bipolar disorder (24.1%, 25.9%). The rate of any metabolic testing was 53.5% in CY2016 and 51.3% in CY2017. Glucose testing (50.3%, 46.9%, respectively) was most common in both CYs, followed by LDL-C testing (31.2%, 28.5%). Rates of combined glucose and lipid metabolism testing were 30.7% in CY2016 and 26.9% in CY2017. Conclusions: Given the known potential for adverse cardiometabolic effects, rates of metabolic monitoring associated with SGA use in children and adolescents urgently need to be improved. There is a critical need for understanding barriers to routine monitoring, particularly of lipids, and developing interventions to enhance metabolic monitoring.

During the process of regeneration, a switch in the transcription program occurs in cells that contribute to the reconstruction of the missing tissue. Early signals released upon damage are integrated into the chromatin of responding cells to change its activity and function. Changes in chromatin dynamics result in transcriptional reprogramming, this is the coordinated regulation of expression of a specific subset of genes required for the regeneration process. Here we summarize changes in gene expression and chromatin dynamics that occurs during the process of regeneration of Drosophila imaginal discs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Identifying correlates of capacity to provide informed consent among individuals with bipolar disorder is essential for patient protection. As part of a clinical trial involving approved, standard treatments, we investigated relationships between clinical characteristics and capacity to provide informed consent in adults with bipolar disorder using the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). After administering the MacCAT-CR, continuing participants in the trial were capable of and provided informed consent., Methods: Trained, board-certified psychiatrists administered the MacCAT-CR to potential study participants (N = 50) after they provided informed consent, but prior to initiation of study procedures., Results: Higher Schedule for Assessment of Positive Symptoms (SAPS) scores were significantly correlated with worse MacCAT-CR Understanding and Appreciation (p < 0.04) subscale scores; lower Hamilton Depression Rating Scale (HDRS) scores and higher Clinical Global Impression-Severity (CGI-S) scores were significantly correlated with worse Reasoning and Understanding subscale scores (p < 0.03); and patients with comorbid substance use disorders (SUD) had better Appreciation and Reasoning subscale scores (p < 0.05)., Limitations: The MacCAT-CR identifies areas where participants need explanation. However, there is not a predetermined score to indicate understanding of study procedures and therefore input from a trained clinician is needed to determine capacity to provide informed consent., Conclusions: Our findings suggest that certain measures of illness severity are associated with lower levels of capacity to provide informed consent among adults with bipolar disorder. This study provides important information for clinicians and researchers to consider when obtaining informed consent in this population., (Copyright © 2018. Published by Elsevier B.V.)

One of the most important questions in regenerative biology is to unveil how and when genes change expression and trigger regeneration programs. The resetting of gene expression patterns during response to injury is governed by coordinated actions of genomic regions that control the activity of multiple sequence-specific DNA binding proteins. Using genome-wide approaches to interrogate chromatin function, we here identify the elements that regulate tissue recovery in Drosophila imaginal discs, which show a high regenerative capacity after genetically induced cell death. Our findings indicate there is global coregulation of gene expression as well as a regeneration program driven by different types of regulatory elements. Novel enhancers acting exclusively within damaged tissue cooperate with enhancers co-opted from other tissues and other developmental stages, as well as with endogenous enhancers that show increased activity after injury. Together, these enhancers host binding sites for regulatory proteins that include a core set of conserved transcription factors that control regeneration across metazoans., (© 2018 Vizcaya-Molina et al.; Published by Cold Spring Harbor Laboratory Press.)

Klebsiella pneumoniae (Kp) is a globally disseminated opportunistic pathogen that can cause life-threatening infections. It has been found as the culprit of many infection outbreaks in hospital environments, being particularly aggressive towards newborns and adults under intensive care. Many Kp strains produce extended-spectrum β-lactamases, enzymes that promote resistance against antibiotics used to fight these infections. The presence of other resistance determinants leading to multidrug-resistance also limit therapeutic options, and the use of 'last-resort' drugs, such as polymyxins, is not uncommon. The global emergence and spread of resistant strains underline the need for novel antimicrobials against Kp and related bacterial pathogens. To tackle this great challenge, we generated multiple layers of 'omics' data related to Kp and prioritized proteins that could serve as attractive targets for antimicrobial development. Genomics, transcriptomics, structuromic and metabolic information were integrated in order to prioritize candidate targets, and this data compendium is freely available as a web server. Twenty-nine proteins with desirable characteristics from a drug development perspective were shortlisted, which participate in important processes such as lipid synthesis, cofactor production, and core metabolism. Collectively, our results point towards novel targets for the control of Kp and related bacterial pathogens.

Background: Total elbow arthroplasty is a treatment for unreconstructable distal humeral fractures; however, longevity of the implant remains a concern in younger, more active patients. Distal humeral hemiarthroplasty (DHH) offers an alternative with multiple advantages., Methods: This is a retrospective study of 10 patients who underwent DHH for distal humeral fractures during a 4-year period (2008-2012) by a single surgeon. Patients underwent testing of range of motion, Mayo Elbow Performance Score, Disabilities of Arm, Shoulder and Hand, visual analog scale, Single Assessment Numeric Evaluation, and American Shoulder and Elbow Surgeons scores. Average patent age at surgery was 71.9 years (range, 56-81 years); average follow-up was 73.2 months (range, 36-96 months)., Results: Patients maintained improvements in Mayo Elbow Performance Scores (mean, 89.23; range, 75-100) and Disabilities of Arm, Shoulder and Hand scores (mean, 33.71; range 11.2-55.1), along with no significant decrease in range of motion compared with 1 year after surgery. Mean visual analog scale was 2.43 (range, 0-5), Single Assessment Numeric Evaluation was 74.14 (range, 50-100), and American Shoulder and Elbow Surgeons score was 72.14 (range, 48.33-100). Participants had an average flexion of 128.7° (range, 95°-142°), extension deficit of 27.1° (range, 0°-45°), supination of 79.1° (range, 45°-90°), and pronation of 73.3° (range, 50°-90°). No heterotopic ossification, elbow dislocations, or subluxations were observed. Complications included 1 fracture and 1 complaint of prominent hardware. Two patients died, and 1 patient was lost to follow-up., Conclusion: This midterm review suggests that DHH may be an effective treatment for certain distal humeral fractures. The data suggest that elbow range of motion and functional use are maintained from comparison with short-term studies. Additional studies must be conducted to further define the role of DHH for complex fractures of the distal humerus., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: What an organism needs at least from its environment to produce a set of metabolites, e.g. target(s) of interest and/or biomass, has been called a minimal precursor set. Early approaches to enumerate all minimal precursor sets took into account only the topology of the metabolic network (topological precursor sets). Due to cycles and the stoichiometric values of the reactions, it is often not possible to produce the target(s) from a topological precursor set in the sense that there is no feasible flux. Although considering the stoichiometry makes the problem harder, it enables to obtain biologically reasonable precursor sets that we call stoichiometric. Recently a method to enumerate all minimal stoichiometric precursor sets was proposed in the literature. The relationship between topological and stoichiometric precursor sets had however not yet been studied., Results: Such relationship between topological and stoichiometric precursor sets is highlighted. We also present two algorithms that enumerate all minimal stoichiometric precursor sets. The first one is of theoretical interest only and is based on the above mentioned relationship. The second approach solves a series of mixed integer linear programming problems. We compared the computed minimal precursor sets to experimentally obtained growth media of several Escherichia coli strains using genome-scale metabolic networks., Conclusions: The results show that the second approach efficiently enumerates minimal precursor sets taking stoichiometry into account, and allows for broad in silico studies of strains or species interactions that may help to understand e.g. pathotype and niche-specific metabolic capabilities. sasita is written in Java, uses cplex as LP solver and can be downloaded together with all networks and input files used in this paper at http://www.sasita.gforge.inria.fr.

Certain trypanosomatids co-evolve with an endosymbiotic bacterium in a mutualistic relationship that is characterized by intense metabolic exchanges. Symbionts were able to respire for up to 4 h after isolation from Angomonas deanei. FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) similarly increased respiration in wild-type and aposymbiotic protozoa, though a higher maximal O2 consumption capacity was observed in the symbiont-containing cells. Rotenone, a complex I inhibitor, did not affect A. deanei respiration, whereas TTFA (thenoyltrifluoroacetone), a complex II activity inhibitor, completely blocked respiration in both strains. Antimycin A and cyanide, inhibitors of complexes III and IV, respectively, abolished O2 consumption, but the aposymbiotic protozoa were more sensitive to both compounds. Oligomycin did not affect cell respiration, whereas carboxyatractyloside (CAT), an inhibitor of the ADP-ATP translocator, slightly reduced O2 consumption. In the A. deanei genome, sequences encoding most proteins of the respiratory chain are present. The symbiont genome lost part of the electron transport system (ETS), but complex I, a cytochrome d oxidase, and FoF1-ATP synthase remain. In conclusion, this work suggests that the symbiont influences the mitochondrial respiration of the host protozoan.

This preliminary study investigated the neurofunctional effects of carbamazepine-extended release (XR) treatment in 11 manic youth with bipolar disorder during performance of a sustained attention task, the Continuous Performance Task - Identical Pairs version (CPT-IP), during functional magnetic resonance imaging (fMRI). All patients underwent baseline fMRI, and 10 patients were scanned again at endpoint. Nine demographically matched healthy youth, who were scanned once, served as controls. Carbamazepine-XR treatment was associated with normalization of activation in right Brodmann area 10 (BA). These results suggest that carbamazepine-XR treatment may correct prefrontal dysfunction in adolescent mania., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Motivation: The increasing availability of metabolomics data enables to better understand the metabolic processes involved in the immediate response of an organism to environmental changes and stress. The data usually come in the form of a list of metabolites whose concentrations significantly changed under some conditions, and are thus not easy to interpret without being able to precisely visualize how such metabolites are interconnected., Results: We present a method that enables to organize the data from any metabolomics experiment into metabolic stories. Each story corresponds to a possible scenario explaining the flow of matter between the metabolites of interest. These scenarios may then be ranked in different ways depending on which interpretation one wishes to emphasize for the causal link between two affected metabolites: enzyme activation, enzyme inhibition or domino effect on the concentration changes of substrates and products. Equally probable stories under any selected ranking scheme can be further grouped into a single anthology that summarizes, in a unique subnetwork, all equivalently plausible alternative stories. An anthology is simply a union of such stories. We detail an application of the method to the response of yeast to cadmium exposure. We use this system as a proof of concept for our method, and we show that we are able to find a story that reproduces very well the current knowledge about the yeast response to cadmium. We further show that this response is mostly based on enzyme activation. We also provide a framework for exploring the alternative pathways or side effects this local response is expected to have in the rest of the network. We discuss several interpretations for the changes we see, and we suggest hypotheses that could in principle be experimentally tested. Noticeably, our method requires simple input data and could be used in a wide variety of applications., Availability and Implementation: The code for the method presented in this article is available at http://gobbolino.gforge.inria.fr.

Some non-pathogenic trypanosomatids maintain a mutualistic relationship with a betaproteobacterium of the Alcaligenaceae family. Intensive nutritional exchanges have been reported between the two partners, indicating that these protozoa are excellent biological models to study metabolic co-evolution. We previously sequenced and herein investigate the entire genomes of five trypanosomatids which harbor a symbiotic bacterium (SHTs for Symbiont-Haboring Trypanosomatids) and the respective bacteria (TPEs for Trypanosomatid Proteobacterial Endosymbiont), as well as two trypanosomatids without symbionts (RTs for Regular Trypanosomatids), for the presence of genes of the classical pathways for vitamin biosynthesis. Our data show that genes for the biosynthetic pathways of thiamine, biotin, and nicotinic acid are absent from all trypanosomatid genomes. This is in agreement with the absolute growth requirement for these vitamins in all protozoa of the family. Also absent from the genomes of RTs are the genes for the synthesis of pantothenic acid, folic acid, riboflavin, and vitamin B6. This is also in agreement with the available data showing that RTs are auxotrophic for these essential vitamins. On the other hand, SHTs are autotrophic for such vitamins. Indeed, all the genes of the corresponding biosynthetic pathways were identified, most of them in the symbiont genomes, while a few genes, mostly of eukaryotic origin, were found in the host genomes. The only exceptions to the latter are: the gene coding for the enzyme ketopantoate reductase (EC:1.1.1.169) which is related instead to the Firmicutes bacteria; and two other genes, one involved in the salvage pathway of pantothenic acid and the other in the synthesis of ubiquinone, that are related to Gammaproteobacteria. Their presence in trypanosomatids may result from lateral gene transfer. Taken together, our results reinforce the idea that the low nutritional requirement of SHTs is associated with the presence of the symbiotic bacterium, which contains most genes for vitamin production.

Background: Trypanosomatids of the genera Angomonas and Strigomonas live in a mutualistic association characterized by extensive metabolic cooperation with obligate endosymbiotic Betaproteobacteria. However, the role played by the symbiont has been more guessed by indirect means than evidenced. Symbiont-harboring trypanosomatids, in contrast to their counterparts lacking symbionts, exhibit lower nutritional requirements and are autotrophic for essential amino acids. To evidence the symbiont's contributions to this autotrophy, entire genomes of symbionts and trypanosomatids with and without symbionts were sequenced here., Results: Analyses of the essential amino acid pathways revealed that most biosynthetic routes are in the symbiont genome. By contrast, the host trypanosomatid genome contains fewer genes, about half of which originated from different bacterial groups, perhaps only one of which (ornithine cyclodeaminase, EC:4.3.1.12) derived from the symbiont. Nutritional, enzymatic, and genomic data were jointly analyzed to construct an integrated view of essential amino acid metabolism in symbiont-harboring trypanosomatids. This comprehensive analysis showed perfect concordance among all these data, and revealed that the symbiont contains genes for enzymes that complete essential biosynthetic routes for the host amino acid production, thus explaining the low requirement for these elements in symbiont-harboring trypanosomatids. Phylogenetic analyses show that the cooperation between symbionts and their hosts is complemented by multiple horizontal gene transfers, from bacterial lineages to trypanosomatids, that occurred several times in the course of their evolution. Transfers occur preferentially in parts of the pathways that are missing from other eukaryotes., Conclusion: We have herein uncovered the genetic and evolutionary bases of essential amino acid biosynthesis in several trypanosomatids with and without endosymbionts, explaining and complementing decades of experimental results. We uncovered the remarkable plasticity in essential amino acid biosynthesis pathway evolution in these protozoans, demonstrating heavy influence of horizontal gene transfer events, from Bacteria to trypanosomatid nuclei, in the evolution of these pathways.

Endosymbiont-bearing trypanosomatids have been considered excellent models for the study of cell evolution because the host protozoan co-evolves with an intracellular bacterium in a mutualistic relationship. Such protozoa inhabit a single invertebrate host during their entire life cycle and exhibit special characteristics that group them in a particular phylogenetic cluster of the Trypanosomatidae family, thus classified as monoxenics. In an effort to better understand such symbiotic association, we used DNA pyrosequencing and a reference-guided assembly to generate reads that predicted 16,960 and 12,162 open reading frames (ORFs) in two symbiont-bearing trypanosomatids, Angomonas deanei (previously named as Crithidia deanei) and Strigomonas culicis (first known as Blastocrithidia culicis), respectively. Identification of each ORF was based primarily on TriTrypDB using tblastn, and each ORF was confirmed by employing getorf from EMBOSS and Newbler 2.6 when necessary. The monoxenic organisms revealed conserved housekeeping functions when compared to other trypanosomatids, especially compared with Leishmania major. However, major differences were found in ORFs corresponding to the cytoskeleton, the kinetoplast, and the paraflagellar structure. The monoxenic organisms also contain a large number of genes for cytosolic calpain-like and surface gp63 metalloproteases and a reduced number of compartmentalized cysteine proteases in comparison to other TriTryp organisms, reflecting adaptations to the presence of the symbiont. The assembled bacterial endosymbiont sequences exhibit a high A+T content with a total of 787 and 769 ORFs for the Angomonas deanei and Strigomonas culicis endosymbionts, respectively, and indicate that these organisms hold a common ancestor related to the Alcaligenaceae family. Importantly, both symbionts contain enzymes that complement essential host cell biosynthetic pathways, such as those for amino acid, lipid and purine/pyrimidine metabolism. These findings increase our understanding of the intricate symbiotic relationship between the bacterium and the trypanosomatid host and provide clues to better understand eukaryotic cell evolution.

Background: A large number of genome-scale metabolic networks is now available for many organisms, mostly bacteria. Previous works on minimal gene sets, when analysing host-dependent bacteria, found small common sets of metabolic genes. When such analyses are restricted to bacteria with similar lifestyles, larger portions of metabolism are expected to be shared and their composition is worth investigating. Here we report a comparative analysis of the small molecule metabolism of symbiotic bacteria, exploring common and variable portions as well as the contribution of different lifestyle groups to the reduction of a common set of metabolic capabilities., Results: We found no reaction shared by all the bacteria analysed. Disregarding those with the smallest genomes, we still do not find a reaction core, however we did find a core of biochemical capabilities. While obligate intracellular symbionts have no core of reactions within their group, extracellular and cell-associated symbionts do have a small core composed of disconnected fragments. In agreement with previous findings in Escherichia coli, their cores are enriched in biosynthetic processes whereas the variable metabolisms have similar ratios of biosynthetic and degradation reactions. Conversely, the variable metabolism of obligate intracellular symbionts is enriched in anabolism., Conclusion: Even when removing the symbionts with the most reduced genomes, there is no core of reactions common to the analysed symbiotic bacteria. The main reason is the very high specialisation of obligate intracellular symbionts, however, host-dependence alone is not an explanation for such absence. The composition of the metabolism of cell-associated and extracellular bacteria shows that while they have similar needs in terms of the building blocks of their cells, they have to adapt to very distinct environments. On the other hand, in obligate intracellular bacteria, catabolism has largely disappeared, whereas synthetic routes appear to have been selected for depending on the nature of the symbiosis. As more genomes are added, we expect, based on our simulations, that the core of cell-associated and extracellular bacteria continues to diminish, converging to approximately 60 reactions.

Background: The type IV secretion system (T4SS) can be classified as a large family of macromolecule transporter systems, divided into three recognized sub-families, according to the well-known functions. The major sub-family is the conjugation system, which allows transfer of genetic material, such as a nucleoprotein, via cell contact among bacteria. Also, the conjugation system can transfer genetic material from bacteria to eukaryotic cells; such is the case with the T-DNA transfer of Agrobacterium tumefaciens to host plant cells. The system of effector protein transport constitutes the second sub-family, and the third one corresponds to the DNA uptake/release system. Genome analyses have revealed numerous T4SS in Bacteria and Archaea. The purpose of this work was to organize, classify, and integrate the T4SS data into a single database, called AtlasT4SS - the first public database devoted exclusively to this prokaryotic secretion system., Description: The AtlasT4SS is a manual curated database that describes a large number of proteins related to the type IV secretion system reported so far in Gram-negative and Gram-positive bacteria, as well as in Archaea. The database was created using the RDBMS MySQL and the Catalyst Framework based in the Perl programming language and using the Model-View-Controller (MVC) design pattern for Web. The current version holds a comprehensive collection of 1,617 T4SS proteins from 58 Bacteria (49 Gram-negative and 9 Gram-Positive), one Archaea and 11 plasmids. By applying the bi-directional best hit (BBH) relationship in pairwise genome comparison, it was possible to obtain a core set of 134 clusters of orthologous genes encoding T4SS proteins., Conclusions: In our database we present one way of classifying orthologous groups of T4SSs in a hierarchical classification scheme with three levels. The first level comprises four classes that are based on the organization of genetic determinants, shared homologies, and evolutionary relationships: (i) F-T4SS, (ii) P-T4SS, (iii) I-T4SS, and (iv) GI-T4SS. The second level designates a specific well-known protein families otherwise an uncharacterized protein family. Finally, in the third level, each protein of an ortholog cluster is classified according to its involvement in a specific cellular process. AtlasT4SS database is open access and is available at http://www.t4ss.lncc.br.

Objectives: The aim of this study was to characterize Neisseria meningitidis strains causing invasive disease in Rio Grande do Sul (RS), during 2003-2005, monitoring the occurrence of hypervirulent lineages, as well as to determine the diversity of PorA VR types for the corresponding isolates and clinical specimens., Methods: Isolates and clinical specimens were characterized by MLST and PorA VR typing., Results: This study demonstrated high prevalence of some hypervirulent lineages and emergence of new ones, including the emergence of lineages W135:P1.5,2:ST-11 complex, and C:P1.22,14-6:ST-103 complex. These lineages are probably responsible for the increasing incidence of serogroups C and W135, despite the overall decrease in serogroup B cases during the period. The most prevalent complex was serogroup B ST-32/ET-5 complex. The most prevalent PorA types found for serogroup B were P1.19,15, P1.7,16, and P1.18-1,3, representing a different distribution of PorA types compared to other states of Brazil., Conclusions: This study highlights the importance of monitoring each population, even within the same country. The different distribution of PorA VR types in RS has implications in vaccine design and efficacy. Detailed and accurate meningococcal characterization is an important element in studies of meningococcal epidemiology, population biology, and evolution and provides information for the design of control strategies.

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input-output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input-output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.

Objective: To induce prolonged motor cortical excitability reductions by transcranial direct current stimulation in the human., Methods: Cathodal direct current stimulation was applied transcranially to the hand area of the human primary motor cortex from 5 to 9 min in separate sessions in twelve healthy subjects. Cortico-spinal excitability was tested by single pulse transcranial magnetic stimulation. Transcranial electrical stimulation and H-reflexes were used to learn about the origin of the excitability changes. Neurone specific enolase was measured before and after the stimulation to prove the safety of the stimulation protocol., Results: Five and 7 min direct current stimulation resulted in motor cortical excitability reductions, which lasted for minutes after the end of stimulation, 9 min stimulation induced after-effects for up to an hour after the end of stimulation, as revealed by transcranial magnetic stimulation. Muscle evoked potentials elicited by transcranial electric stimulation and H-reflexes did not change. Neurone specific enolase concentrations remained stable throughout the experiments., Conclusions: Cathodal transcranial direct current stimulation is capable of inducing prolonged excitability reductions in the human motor cortex non-invasively. These changes are most probably localised intracortically.